Employing functionalized fragment libraries to identify therapeutic agents for neurofibromatosis type 2

利用功能化片段库来鉴定 2 型神经纤维瘤病的治疗药物

• 批准号: 10704416
• 负责人: JOSEPH KISSIL
• 金额: $ 41.57万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704416
• 关键词: Employing; functionalized; fragment; libraries; identify

Neurofibromatosis type 2 (NF2) is a dominantly inherited autosomal disease with the most common manifestation being development of bilateral schwannomas of the 8th cranial nerve (Vestibular schwannoma). The majority of NF2 patients develop additional tumors throughout the nervous system, including schwannomas, meningiomas and ependymomas, causing severe morbidity and early mortality. The NF2 tumor suppressor gene encodes for a 69-kDa protein called Merlin, implicated in the regulation of a number of signaling pathways, such as those regulated by small G-proteins and the Hippo-YAP signaling pathway. Although our understanding of the molecular mechanisms underlying NF2 has improved over the past two decades, effective therapies remain lacking. To date, systematic efforts to identify therapeutic agents for NF2 have demonstrated limited success, resulting in identification of a small number of candidates that displayed minimal selectivity towards NF2-deficient cells. Arguably, the reasons for this limited success stem from a number of factors including the fact these efforts relied on approaches utilizing traditional screening assays performed with cells plated on plastic dishes, in 2- dimensional (2D) monolayer formats. These conditions poorly reflect the environment cells experience in vivo. In addition, previous screens were performed against a small collection of compounds that were pre-selected based on drug-likeness, known pharmacology, regulatory status, etc. Thus, only limited chemical space has been explored in these efforts. Our long-term goals are to identify small molecules that selectively inhibit NF2-null Schwann cells and optimize these into lead molecules that will be developed into therapeutic agents. Towards this goal we will implement a screening campaign that incorporates a number of innovations that we already demonstrated to dramatically improve discovery efforts. We hypothesize that the proposed research campaign will identify pharmacologically tractable targets/pathways in NF2-null cells, which will be developed as leads for therapeutic development.

2 型神经纤维瘤病 (NF2) 是一种显性遗传的常染色体疾病，最常见 表现为第 8 脑神经双侧神经鞘瘤（前庭神经鞘瘤）。 大多数 NF2 患者会在整个神经系统中出现其他肿瘤，包括神经鞘瘤、 脑膜瘤和室管膜瘤，导致严重发病和早期死亡。 NF2抑癌基因 编码一种名为 Merlin 的 69 kDa 蛋白质，该蛋白质参与许多信号通路的调节，例如 如那些受小 G 蛋白和 Hippo-YAP 信号通路调节的蛋白。虽然我们的理解 NF2的分子机制在过去二十年中得到了改善，但有效的治疗方法仍然存在 缺乏。 迄今为止，识别 NF2 治疗药物的系统性努力已取得有限的成功，导致 鉴定少数对 NF2 缺陷细胞表现出最低选择性的候选细胞。 可以说，这种有限成功的原因源于许多因素，包括这些努力依赖于 利用传统的筛选测定方法，将细胞铺在塑料培养皿上进行，2- 维度（2D）单层格式。这些条件很难反映细胞在体内经历的环境。 此外，之前的筛选是针对预先选择的一小部分化合物进行的 基于药物相似性、已知药理学、监管状态等。因此，只有有限的化学空间 在这些努力中进行了探索。 我们的长期目标是识别选择性抑制 NF2 缺失雪旺细胞的小分子并优化 这些成为将被开发成治疗剂的先导分子。为了实现这一目标，我们将实施 筛选活动包含了我们已经显着展示的许多创新 改进发现工作。我们假设拟议的研究活动将在药理学上确定 NF2 缺失细胞中易于处理的靶点/途径，将被开发为治疗开发的先导。